Wang Hong, Zhao Beili, Huang Lei, Zhu Xiangbin, Li Na, Huang Can, Han Zhen, Ouyang Kunfu
Central Laboratory, Peking University Shenzhen Hospital, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Peking University, Shenzhen, 518036, China.
Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518036, China.
J Gastroenterol. 2025 Feb;60(2):152-165. doi: 10.1007/s00535-024-02164-1. Epub 2024 Oct 30.
Inositol 1,4,5-trisphosphate receptor type 1 (IPR1) has been proposed to play a physiological role in regulating gastrointestinal (GI) motility, but the underlying cell-dependent mechanism remains unclear. Here, we utilized cell-specific IPR1 deletion strategies to address this question in mice.
Conditional IPR1 knockout mice using Wnt1-Cre, Islet1-Cre mice, and smMHC-Cre were generated. Cell lineage tracing was performed to determine where gene deletion occurred in the GI tract. Whole-gut transit assay and isometric tension recording were used to assess GI function in vivo and in vitro.
In the mouse GI tract, Islet1-Cre targeted smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs), but not enteric neurons. IPR1 deletion by Islet1-Cre (isR1KO) caused a phenotype of intestinal pseudo-obstruction (IPO), evidenced by prolonged whole-gut transit time, enlarged GI tract, abdominal distention, and early lethality. IPR1 deletion by Islet1-Cre not only reduced the frequency of spontaneous contractions but also decreased the contractile responses to the muscarinic agonist carbachol (CCh) and electrical field stimulation (EFS) in colonic circular muscles. By contrast, smMHC-Cre only targeted SMCs in the mouse GI tract. Although IPR1 deletion by smMHC-Cre (smR1KO) also reduced the contractile responses to CCh and EFS in colonic circular muscles, the frequency of spontaneous contractions was less affected, and neither global GI abnormalities nor early lethality was found in smR1KO mice.
IPR1 deletion in both ICCs and SMCs but not in SMCs alone causes an IPO phenotype, suggesting that IPR1 in ICCs plays an essential role in regulating GI motility in vivo.
1,4,5-三磷酸肌醇受体1型（IPR1）被认为在调节胃肠（GI）动力方面发挥生理作用，但其潜在的细胞依赖性机制仍不清楚。在此，我们利用细胞特异性IPR1缺失策略在小鼠中解决这个问题。
构建了使用Wnt1-Cre、Islet1-Cre小鼠和smMHC-Cre的条件性IPR1敲除小鼠。进行细胞谱系追踪以确定基因缺失在胃肠道中的位置。采用全肠道转运试验和等长张力记录来评估体内和体外的胃肠功能。
在小鼠胃肠道中，Islet1-Cre靶向平滑肌细胞（SMC）和Cajal间质细胞（ICC），但不靶向肠神经元。Islet1-Cre介导的IPR1缺失（isR1KO）导致肠假性梗阻（IPO）表型，表现为全肠道转运时间延长、胃肠道扩张、腹胀和早期致死率。Islet1-Cre介导的IPR1缺失不仅降低了结肠环行肌的自发收缩频率，还降低了对毒蕈碱激动剂卡巴胆碱（CCh）和电场刺激（EFS）的收缩反应。相比之下，smMHC-Cre仅靶向小鼠胃肠道中的SMC。虽然smMHC-Cre介导的IPR1缺失（smR1KO）也降低了结肠环行肌对CCh和EFS的收缩反应，但自发收缩频率受影响较小，且smR1KO小鼠未发现整体胃肠异常或早期致死率。
ICC和SMC中而非仅SMC中的IPR1缺失导致IPO表型，提示ICC中的IPR1在体内调节胃肠动力中起重要作用。
